Recently, the team of Prof. Chen Xiang and Prof. Peng Cong from the Department of Dermatology of Xiangya Hospital of Central South University, Hunan Key Laboratory of Skin Cancer and Psoriasis, Hunan Engineering Research Center of Skin Health and Disease and Xiangya Clinical Research Center for Cancer Immunotherapy of Central South University published six high-quality papers on top-notch journals, including two papers published onResearch(IF=11.000),and the rest four published onJournal of the European Academy of Dermatology and Venereology(IF=9.200),Medcomm(IF=9.900),Cell Death & Disease(IF=9.000) andJournal for Immunotherapy of Cancer(IF=10.900). These studies, through mechanism research and sequencing analysis, revealed the disease characteristics of psoriasis and melanoma to provide new strategies for treatment.
The original paper titled “Lysophosphatidylcholine facilitates the pathogenesis of psoriasis through activating keratinocytes and T cells differentiation via glycolysis” was published on theJournal of the European Academy of Dermatology and Venereology(CAS Q1, IF=9.200). Although abnormal metabolism plays a critical role in the pathogenesis of psoriasis, the details are still unclear. It was found in this study that the level of lysophosphatidylcholine (LPC) and theexpression level of its receptor G2A were elevated in the skin lesions of psoriasis patients. LPC exacerbated mouse psoriasis-like dermatitis models, resulting in an increase in glycolysis level in the skin lesions. Mechanistically, LPC activates STAT1, and promotes the expression of key enzymes (GCK/PKLR) of glycolysis, thus increases the glycolysis level in keratinocytes, and makes inflammatory factors released. In addition, LPC accelerates the process of glycolysis promoting Th1 differentiation, and induces Th17 differentiation by stimulating the release of IL-1β from keratinocytes. The study revealed the role of the LPC/G2A axis in regulating glycolysis to promote the development and progression of psoriasis, providing a potential strategy for targeted LPC/G2A therapy for psoriasis. Postdoctoral fellow Liu Panpan from Xiangya Hospital is the single first author. Prof. Chen Xiang and Prof. Peng Cong from Xiangya Hospital are the co-corresponding authors.
The original paper titled “CD147 Facilitates the Pathogenesis of Psoriasis through Glycolysis and H3K9me3 Modification in Keratinocytes” was published on theResearch(a top journal in CAS Q1, IF=11.000). The team has previously confirmed that CD147 is a susceptibility gene for psoriasis. CD147 was highly expressed in human psoriasis lesions and imiquimod (IMQ)-induced mouse psoriasis-like lesions, playing a pro-inflammatory role in the IL-22-mediated signaling pathway. However, the metabolic and immunological mechanisms of epidermal CD147 in the pathogenesis of psoriasis are not clear. Therefore, in this study, the research team designed epidermis-specific CD147 gene knockout mice (K14.Bsgfl/fl mice), and used the IMQ-induced mouse psoriasis-like dermatitis model to analyze the non-targeted metabolomics and targeted metabolomics data. It was found that CD147 can regulate keratinocyte metabolic reprogramming through the α-KG-H3K9me3-BBOX1 axis to promote the development and progression of psoriasis. This suggests that epidermal CD147 and its downstream metabolism and immune signaling pathways may be new targets for treatment of psoriasis, providing new ideas for treatment of psoriasis. Dr. Chen Chao from Xiangya Hospital is the single first author. Prof. Chen Xiang, Prof. Peng Cong and Prof. Zhu Wu from Xiangya Hospital are the co-corresponding authors.
The original paper titled “TRAF6 regulates autophagy and apoptosis of melanoma cells through c-Jun/ATG16L2 signaling pathway” was published on theMedcomm(JCR Q1, IF=9.900).Autophagy and apoptosis are essential processes that participate in cell death and maintain cellular homeostasis. Dysregulation of these biological processes results in the development of diseases, including cancers. Previous studies by the team have confirmed that tumor necrosis factor receptor-associated factor 6 (TRAF6) is highly expressed in melanoma and promotes malignant phenotype of cells. However, the functions and mechanisms of TRAF6 in cell autophagy and apoptosis are still unclear. This study first demonstrated that TRAF6 is involved in autophagy and apoptosis of melanoma cells. Genomic data analysis revealed that TRAF6 can regulate the expression of autophagy-associated gene ATG16L2, and further elucidated the molecular mechanism of TRAF6/c-Jun/ATG16L2 in regulating cell autophagy; additionally, the TRAF6 inhibitor Cinchonine was found to induce autophagy of melanoma cells to inhibit the proliferation of melanoma cells both in vitro and in vivo. All these findings provide a new potential strategy for clinical treatment. Postdoctoral fellow Guo Yeye and assistant researcher Zhang Xu from Xiangya Hospital are the co-first authors. Prof. Chen Xiang and Prof. Peng Cong from Xiangya Hospital are the co-corresponding authors.
The original paper titled “Supplementation with α-ketoglutarate improved the efficacy of anti-PD1 melanoma treatment through epigenetic modulation of PD-L1” was published on theCell Death & Disease(a top journal in CAS Q1, IF=9.000). Patients with advanced melanoma have shown an improved outlook after anti-PD1 therapy, but the low response rate restricts clinical benefit; therefore, enhancing anti-PD1 therapeutic efficacy remains a major challenge. The research team’s results showed a significantly increased abundance of α-KG in healthy controls, anti-PD1-sensitive melanoma-bearing mice, and anti-PD1-sensitive melanoma patients; moreover, supplementation with α-KG enhanced the efficacy of anti-PD1 immunotherapy and increased PD-L1 expression in melanoma tumors via STAT1/3. They also found that supplementation with α-KG significantly increased the activity of the methylcytosine dioxygenases TET2/3, which led to an increased 5-hydroxymethylcytosine (5-hmC) level in the PD-L1 promoter. As a consequence, STAT1/3 binding to the PD-L1 promoter was stabilized to upregulate PD-L1 expression. Single-cell sequencing of preclinical samples and analysis of clinical data revealed that TET2/3-STAT1/3-CD274 signaling was associated with the sensitivity to anti-PD1 treatment in melanoma. The research results provide new insights into the role of α-KG in anti-PD1 melanoma treatment, and suggest supplementation with α-KG is as a promising new strategy to improve the efficacy of anti-PD1 treatment. Postdoctoral fellow Liu Nian from Xiangya Hospital is the single first author. Prof. Chen Xiang and Prof. Peng Cong from Xiangya Hospital are the co-corresponding authors.
The original paper titled “Eubacterium Rectale Improves the Efficacy of Anti-PD1 Immunotherapy in Melanoma via L-Serine-Mediated NK Cell Activation” was published on theResearch(a top journal in CAS Q1, IF=11.000). Natural killer (NK) cells, as key immune cells, play essential roles in tumor cell immune escape and immunotherapy. Accumulating evidence has demonstrated that the gut microbiota community affects the efficacy of anti-PD1 immunotherapy and that remodeling the gut microbiota is a promising strategy to enhance anti-PD1 immunotherapy responsiveness in advanced melanoma patients; however, the details of the mechanism remain elusive. In this study, it was found that Eubacterium rectale was significantly enriched in melanoma patients who responded to anti-PD1 immunotherapy and that a high E. rectale abundance was related to longer survival in melanoma patients. Furthermore, administration of E. rectale remarkably improved the efficacy of anti-PD1 therapy and increased the overall survival of tumor-bearing mice; moreover, application of E. rectale led to a significant accumulation of NK cells in the tumor microenvironment. Gas chromatography–mass spectrometry/ultrahigh performance liquid chromatography–tandem mass spectrometry-based metabolomic analysis showed that L-serine production was significantly decreased in the E. rectale group; moreover, administration of an L-serine synthesis inhibitor dramatically increased NK cell activation, which enhanced anti-PD1 immunotherapy effects. The results of this study revealed the role of E. rectale in regulating serine metabolic signaling in NK cell activation, providing a new therapeutic strategy for improving the efficacy of anti-PD1 immunotherapy in melanoma. Postdoctoral fellow Liu Nian and graduate student Chen Lihui from Xiangya Hospital are the co-first authors. Prof. Chen Xiang, Prof. Peng Cong, and Prof. Zhang Wei from Xiangya Hospital are the co-corresponding authors.
The original paper titled “Inhibition of TCA cycle improves the anti-PD1 immunotherapy efficacy in melanoma cells via ATF3-mediated PD-L1 expression and glycolysis” was published on theJournal for Immunotherapy of Cancer(JCR Q1, IF=10.900). Although the metabolic alterations from tricarboxylic acid (TCA) cycle to glycolysis is a hallmark of cancer cells, accumulating evidence suggests that TCA cycle plays a critical role in both tumorigenesis and treatment. The research results showed that significant alterations in metabolites associated with glycolysis and the TCA cycle in plasma of patients with melanoma through NMR technique, and then, pyruvate dehydrogenase subunit 1 (PDHA1) and oxoglutarate dehydrogenase (OGDH), key enzymes for regulation TCA cycle, were remarkable raised in melanoma and negatively related to anti-PD-1 efficacy through clinical database analysis as well as ScRNA-Seq. Inhibition of PDHA1 and OGDH by either shRNA or pharmacological inhibitor by CPI613 dramatically attenuated melanoma progression as well as improved the therapeutic efficacy of anti-PD-1 against melanoma. Suppression of TCA cycle remarkably raises PD-L1 expression and glycolysis flux through AMPK-CREB-ATF3 signaling. The research results of the team demonstrated the role of TCA cycle in immune checkpoint blockade (ICB), providing a new combination strategy for anti-PD-1 immunotherapy in melanoma treatment. Postdoctoral fellow Liu Nian from Xiangya Hospital is the single first author. Prof. Chen Xiang and Prof. Peng Cong from Xiangya Hospital are the corresponding authors.
Prof. Peng Cong, the Leading Talent of scientific and technological innovation of the "Ten Thousand Talents Plan", the Leading Talent of scientific and technological innovation in Hunan Province, the “Distinguished Professor” of Sublimation Scholar Program of Central South University and the Deputy Director of the Hunan Key Laboratory of Skin Cancer and Psoriasis, is dedicated to the research on metabolic regulation, molecular mechanisms and screening of small molecule inhibitors for major skin diseases. In the past three years, he has published more than 40 papers as the first/corresponding author in well-known journals such asSig Trans Tar Ther, Nat Comm, PNAS, Theranostics, Molecular TherapyandJ Invest Dermatol. He has also led multiple national-level projects. Backed by Xiangya Hospital of Central South University, Hunan Key Laboratory of Skin Cancer and Psoriasis, Hunan Engineering Research Center of Skin Health and Disease and Xiangya Clinical Research Center for Cancer Immunotherapy constitute a research platform focusing on clinical issues. Their research teams are committed to studying the basic and translational research about major skin diseases like skin cancer, psoriasis and allergic skin diseases. Adhering to the development concepts of “Science, Rigor, Passion, Cooperation”, the research teams attract National High-Level Talents, National Distinguished Young Scholars and Changjiang Scholars as leaders, and National Excellent Young Scholars, National Young Top-notch Talent and Hunan Young Talents as the backbone. The teams remain committed to clinical research on psoriasis, melanoma and other major skin diseases, in an effort to promote the growth of the Department of Dermatology into a first-class discipline at Xiangya Hospital.
Source: Xiangya Hospital of Central South University; Author: -
